17-(aliphatic hydrocarbonthio)- and 17-(substituted aliphatic hydrocarbon-thio) estrane derivatives



United States Patent 17-(ALIPHATIC HYDROCARBONTHIO)- AND 17- (SUBSTITUTED ALIPHATIC HYDRDCARBON- THIO)ESTRANE DERIVATIVES Alexander D. Cross, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed May 24, 1963, Ser. No. 282,847

27 Claims. (Cl. 260--397.1)

This invention relates to novel cyclopentanopolyhydrophenanthrene derivatives and to processes for their preparation.

More particularly, this invention relates to novel 17- (aliphatic hydrocarbonthio)- and 17-(substituted aliphatic hydrocarbonthio)estrane derivatives represented by the general formulas:

In these formulas, R represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon residue containing from 1 to carbon atoms, inclusive, such as ethylene, i.e., CH CH propylene, butylene, hexamethylene, octamethylene, isooctale'ne, 2,3-dimethylheptalene, 2-methyl-3-ethylheptalene, but-l-enylene, 2- methylbut-2-enylene, but-l-inylene, isooct-Z-enylene, 2,3- dimethylhept-Z-enylene, 2-methyl-3-ethylhept-2-enylene, and the like, with R preferably being ethylene in Formula B; the group OR represents a hydroxyl group, an acyloXy group or an ether group, i.e., R represents hydrogen, an acyl group, or a saturated or unsaturated, straight or branched chain aliphatic, cycloaliphatic or aromatic-aliphatic group containing from 1 to 12 carbon atoms, inelusive, and preferably a hydrocarbon group containing up to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, isoamyl, n-decyl, cyclohexyl, cyclohexenyl, benzyl, and the like, and R represents hydrogen or methyl.

In the grouping 0R which is substituted on a primary, secondary or tertiary carbon atom of the group R, R represents hydrogen or an acyl group The symbol X represents hydrogen, a halogen, e.g., fluorine or chlorine, an N,N-dialkylamino group, preferably an N,N-di(lower) alkylamino group such as N,N-dimethylamino and the like, a carboxyl group, a cyano group, or an aldehydic oxygen (i.e., an oxygen atom doubly bonded to a carbon atom of the group R, said carbon atom also having a hydrogen atom attached thereto).

The symbol Z represents a saturated linkage or a double bond at the 6,7-position in this steroid nucleus.

This invention further relates to a novel l7-(aliphatic hydrocarbonthio)- and 17-(substituted aliphatic hydrocarbonthio)-A -estren-3-ones, obtained from said 17-(aliphatic hydrocarbonthio)- and l7-(substituted aliphatic hydrocarbonthio)estrane derivatives and represented by the general formulas:

In these formulas R and R have the same meanings as set forth hereinabove for Formulas A and B, with R preferably being ethylene in Formula D, and Y represents hydrogen, a halogen, e.g., fluorine or chlorine, or an N,N-dialkylamino group, preferably an N,N-di(lower)alkylamino group such as N,N-dimethylamino and the like.

The symbol 5 at the l7-position in the above formulas and in those that follow signifies that the aliphatic hydrocarbonthio or substituted aliphatic hydrocarbonthio substituent at the ,1-7-position can be in either the ocor the t?- configuration.

The acyl and acyloxy groups referred to hereinabove are derived from carboxylic acids, preferably hydrocarbon carboxylic acids, of less than 12 carbon atoms. These acids can be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted with functional groups such as hydroxyl groups, alkoxy groups containing up to 5 carbon atoms, acyloxy groups containing up to 12 carbon atoms, nitro groups, amino groups and halogens. Typical ester groups are the acetate, trimethylacetate, t-butylacetate, aminoacetate, phenoxyacetate, propionate, fi-chloropropionate, cyclopentylpropionate, enanthate and benzoate.

The novel l7-(aliphatic hydrocarbonthio)- and 17- (substituted aliphatic hydrocarbonthio)--A -estratrienes represented by Formula A above have remarkable estrogenic activity, and are useful in fertility control and in lowering cholesterol levels in blood. In addition, they serve as intermediates for the preparation of the compounds of Formulas B and C.

The novel l7-(aliphatic hydrocarbonthio)- and 17- (substituted aliphatic hydrocarbonthio)-A -estra= trienes represented by Formula B above are also strong estrogenic agents with enhanced blood chloresteroldowering activity. In addition, they serve as intermediates for the preparation of the compounds of Formula D.

The novel l7-(aliphatic hydrocarbontln'o)- and 17- (substantial aliphatic hydrocarbonthio)-L\ -estren-3-ones represented by Formulas C and D above are anabolic-androgenic agents having a favorable anabolic-androgenic ratio. They also have anti-estrogenic, anti-gonadotropic, anti-fibrillatory and appetite-stimulating properties, and further serve to lower blood cholesterol. levels, relieve premenstrual tension and suppress the output of the pituitary gland.

The compounds of the present invention can be obborohydride, potassium borohydride, aluminum borohy- 3 tained by the method illustrated by the following se quence of reactions:

i SR-OR8 E 2 o go a no a S-R-OR3 V E Z 1 l3 I3 v1 7 v i In the above formulas each of R, R, R R X, Y and Z have the same meanings as set forth hereinabove for Formulas A-D.

In practicing the method outlined above, the estrone derivative (I) employed as the starting material, e.g., estrone methyl ether, is reacted with a monothioglycol of up to 10 carbon atoms, such as fl-mercaptoethanol, 'y-mercaptopropanol, 1-mercaptopropanol-2, fi-mercaptobutanol, and the like, to yield the corresponding 17-monothioketal (II), e.g., l7-(cycloethylenethioxy)-3-methox- A -estratriene. This reaction will generally be carried out in the presence of a strong acid, e.g., p-toluenesulfonic acid, preferably in solution in an inert organic solvent such as benzene and the like, at reflux temperature, and will usually take about 16 hours, although longer or shorter reaction times coupled with lower or higher temperatures may be employed if desired.

The monothioketal (II) is then heated with a cleaving agent, as described in my copending US. patent application Serial No. 282,848, filed on May 24, 1963, e.g., a double metal hydride containing at least one element of sub-group IIIA of the Periodic Chart [as set forth at pages 56 and 57 of Langes Handbook of Chemistry, Ninth Edition (Sandusky,- Ohio, Handbook Publishers, Inc., 1956)], suchas lithium aluminum hydride, potassium aluminum hydride, magnesium aluminum hydride, lithium gallium hydride, zinc aluminum hydride, sodium dride, and the like, together with a Lewis acid containing no active hydrogen, and preferably a Lewis acid containing an element having an atomic number of 26 to 28 inclusive or an element of sub-group IIIA or" the Periodic Chart, such as vferric chloride, boron trifluoride, boron 7 hydrocarbonthio)-A -estratrienes, e.g.,

trichloride, aluminum fluoride, aluminum chloride, aluminum bromide, gallium chloride, and the like, to yield the corresponding 17aand l7fl-(hydroxy aliphatic hydrocarbonthio)-A -estratrienes (III; R =H), e.g., and l7fl-(2-hydroxyethylthio)-3-methoxy-A -estratriene being obtained by reacting l7-(cycloethylenethiooxy)-3-methoxy-A -estratriene with lithium aluminum hydride and aluminum chloride in tetrahydrofuran. This reaction will generally be carried out in an organic solvent having an ether function in its molecule, e.g., diethyl ether, tetrahydrofuran, and the like, at a temperature ranging from room temperature (about 25 C.) or lower to reflux temperature or above for a period of time ranging anywhere from about 30 minutes to about 24 hours. The 1705- and 17,6-derivatives can be separated by conventional chromatographic methods.

These 171xand 17B-(hydroxy aliphatic hydrocarbonthio)-A -estratrienes, e.g., 17aand 17fl-(2'-hydroxyethylthio)-3-methoXy-A -estratriene, when tosylated by known procedures, e.g., using tosyl chloride in pyridine, yield the corresponding l7-(tosyl-oxy aliphatic 1704-, and 17fl-(2-tosyloxyethylthio) 3 methoxy-A -estratriene.

These tosylated intermediates, when treated at reflux temperature with an alkali metal halide, such as lithium chloride, potassium fluoride, potassium chloride, sodium chloride, and the like, preferably in an inert organic solvent such as dimethyl formamide and the like, yield the corresponding l7-(halo aliphatic hydrocarbonthio)- n -estratrienes (IV; X=halogen), e.g., 170aand 17,8 (2-fiuoroethylthio)-3-methoxy-A -estratriene being obtained by reacting 1711- and 17fi-(2'-tosyloxyethylthio)-3-methoxy-A -estratriene with potassium fluoride.

Similarly, treatment of the 17-(tosyloxy aliphatic hydrocarbonthio)-estratriene intermediates with a dialkylamine, preferably a di(lower)alkylamine such as dimethylamine, diethylamine, methyl propylamine, and the like, preferably in solution in an inert organic solvent such as dioxane and the like, gives the corresponding 17ocand 17fl-(N,N-

dialkylamino aliphatic hydrocarbonthio)-A -estratrienes [IX; X=N(alkyl) e.g., 17aand 17,B-[2-(N,N- dimethylamino) ethylthio] 3-methoxy-A -estratriene.

Treatment of the tosyloxy intermediates with an alkali metal cyanide, e.g., sodium cyanide, potassium cyanide, and the like, preferably in solution in an inert organic solvent such as acetonitrile and the like, produces the corresponding 170C- and l7B-(cyano aliphatic hydrocarbonthio-(A -estratrienes (IV; X=CN), e.g., 17aand 17B-(2'-cyanoethylthio)-3-methoxy-A -estratriene.-

These 17-(cyano aliphatic hydrocarbonthio) compounds, when subjected to conventional basic hydrolysis, e.g., using aqueous sodium hydroxide or the like, alford the corresponding 17aand l7fi-(carboxy aliphatic hydrocarbonthio)-A -estratrienes (IV; X=COOH), e.g., 17zxand 17/3 (2' carboxyethylthio)3;methoxyn -estratriene being obtained by hydrolyzing 17aand 175-(2-cyanoethylthio)-3-methoxy-A -estratriene.

Treatment of the 17-(carboxy aliphatic hydrocarbonthio) compounds with a lower alkyl magnesium halide,

such as methyl magnesium bromide and the like, under,

conventional conditions, produces the corresponding 17aand 17B-(n-hydroxy-n-alkyl aliphatic hydrocarbonthio) A )-e tratrienes (III; R =II), n being the carbon atom of the aliphatic hydrocarbonthio group to which the hydroxy and alkyl groups are attached, e.g., 17aand 17b- (3 hydroxy 3'-methylbutylthio)-3-methoxy-A estratriene being the products resulting from the reaction of 1700- and 17,8-(2-carboxyethylthio)-3-methoxy-A -estratriene with methyl magnesium bromide. Dehydra'tion of these 17-(n-hydroxy-n-alkyl aliphatic hydrocarbonthio) intermediates, for example by treatment with mesyl chloride in dimethyl formamide-pyridine at about 80 C. for about 3 hours, results in the corresponding 17aand Uri-(unsaturated aliphatic hydrocarbonthio)-A estratrienes (IV; X=H, R is unsaturated), e.g., 1711- and 17B- (3 -hydroxy-3'-methyl-butylthio -3 -methoxy-A estratriene yielding, on dehydration, 17w and 175-6- methylbut 2'-enylthio)-3-methoxy-A -estratriene. Catalytic hydrogenation of these 17-(unsaturated aliphatic hydrocarbonthio)-A -estratrienes, e.g., at atmospheric pressure using a 5% palladium-on-charcoal catalyst; results in the corresponding l7ocand IKE-(saturated aliphatic hydrocarbonthio)-A -estratrienes (IV; X=H, R is saturated), e.g., 17OL- and l75-3-methyl-but-2'-enylthio)-3-methoxy-A -estratriene, upon catalyticall hydrogenation, yield l7ocand 17,8-(isoamylthio)-3-methoxy-A -estratriene.

Oxidation of a l7-(hydroxy aliphatic hydrocarbonthio) A -estratriene (III; R =H), e.g., 1706- or 17,842- hydroxyethylthio)-3-methoxy-A -estratriene, preferably using chromium trioxide in pyridine, gives the corresponding 17-(oxoaliphatic hydrocarbonthio)-A -estratriene (IV; X=aldehydic oxygen), e.g., 171xor 175- (2 oxoethylthio-3-methoxy-A -estratriene. These 17-(oxoaliphatic hydrocarbonthio) derivatives, when treated with a lower alkyl, lower alkenyl or lower alkinyl magnesium halide, such as methyl magnesium bromide, vinyl magnesium bromide, ethinyl magnesium bromide, and the like, using conventional conditions, yield the corresponding 17aand 175-[n'-hydroxy-n'-lower (alkyl, alkenyl or alkinyl) aliphatic hydrocarbonthio]-A -estratrienes (III- X=H, R is saturated or unsaturated), 11' again being the carbon atom of the aliphatic hydrocarbonthio group to which the hydroxy and lower alkyl, alkenyl or alkinyl groups are atached, e.g., 17: and 17;?- (2' hydroxypropylthio)-3-methoxy-A -estratriene, 171 and 17B (2' hydroxybut-3-enylthio)-3-methoxy- A -estratriene and 17m and 17B-(2-hydr0xybut-3- inylthio)-3-methoxy-A -estratriene resulting from the reaction of 17aand 17B-(2-oxoethylthio)-3-methoxy- A -estratriene with methyl, vinyl and ethinyl magnesium bromide, respectively.

The 3-ethers of the novel 17-(aliphatic hydrocarbonthioand l7-substituted aliphatic hydrocarbonthio- A -estratrienes (III and IV; R=H, acyl), and preferably those wherein R represents hydrogen, Z represents a saturated linkage at the 6,7-position and X represents hydrogen or N,N-dialkylamino, are readily converted to the corresponding l7-(aliphatic hydrocarbonthio)- and 17 (substituted aliphatic hydroearbonthio)-A -estren-3- ones. This can be accomplished, for example, by first reacting the starting A -estratriene, e.g., l7aor 17,8- (isoamylthio) 3-rnethoxy-A -estratriene, with an alkali metal, e.g., lithium, in liquid ammonia, then diluting the reaction mixture with ethanol to give the corresponding o -estradiene intermediate, e.g., 17w or 175- (isoarnylthio) -3-methoxy-A -estradiene, and finally hydrolyzing this A -intermediate with a mineral acid such .as hydrochloric acid and the like to produce the corresponding 17-(aliphatic hydrocarbonthio)- and 17 (substituted aliphatic hydrocarbonthio)-A estren-3- ones (V and VI), e.g., 17ocor 17B-(isoamylthio)-A estren-S-one.

The novel l7-(halo aliphatic hydrocarbonthio-u -estren- 3-ones of the present invention, e.g., the l7-(2haloethylthio)-A -estren-3-ones (VI; Y=halo), are preferably obtained by first tosylating the corresponding l7-(hydroxy aliphatic hydrocarbonthio)-A -estren-3-ones and then reacting the tosylated intermediates with an alkali metal halide in the manner described hereinabove.

The compounds of the present invention having a primary, a secondary or a phenolic hydroxyl group, for example, the compounds represented by Formula I above wherein R represents hydrogen or the compounds of Formula III above wherein OR represents a primary or secondary hydroxyl group, are preferably acylated by reaction with a suitable acid chloride or anhydride in pyridine in the manner well known in the art. Similarly, the compounds of the present invention having a tertiary hydroxyl group, for example, the compounds represented by Formula III above wherein OR represents a tertiary hydroxyl group, are preferably esterified by reaction with a suitable acid anhydride in pyridine, in the presence of an acid catalyst such as p-toluenesulfonic acid and the like, in the manner well known in the art.

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

PREPARATION 1 To a suspension of 25 g. of l-methyl estrone in 25 cc.

of acetone there was added a solution of 70 g. of potassium hydroxide in 37.5 cc. of water and the stirred mixture was treated dropwise with 40 cc. of methyl sulfate. The reaction mixture was then stirred for 45 minutes further, poured into dilute hydrochloric acid solution and the formed precipitate collected by filtration. The collected solid was washed with water to neutral, and dried under reduced pressure. Chromatography of the dry residue on 300 g. of alumina, followed by crystallization of the solid fractions eluted from a mixture of chloroformmethanol, furnished the methyl ether of l-methyl estrone.

Following the same procedure there Were treated:

A -dehydroestrone and 1-methyl-A -dehydroestrone,

thus yielding respectively:

The methyl-ether of A -dehydroestrone and The methyl-ether of 1-methy1-A dehydroestrone.

Example I A mixture of 1 g. of estrone methyl ether, 25 cc. of dry benzene, 5 g. of B-mercapto ethanol, 5t) mg. of p-toluenesulfonic acid monohydrate, was refluxed for 16 hours using a water separator. It was then washed with a sodium bicarbonate solution, water and subsequently dried and evaporated to dryness. Recrystallization from acetone-hexane yielded 17-(cycloethylenethiooxy)-3-methoxy-A -estratriene (Compound No. 11).

Example 11 A solution of 1 g. of Compound No. l in 50 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of l g. of lithiumaluminum hydride and 6 g. of aluminum trichloride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered oil and thoroughly Washed with hot ethyl acetate; the combined organic solutions upon evaporation yielded a crude material, which after chromatography and crystallization of the solid fractions from acetone-hexane aiforded two products; predominantly 17,8 (2' hydroxyethylthio) 3 methoxy- A -estratriene (Cpd. No. 2) and l'iot-(Z-hydroxyethylthio)-3-methoxy-A -estratriene (Cpd. N0. 3) in smaller amount.

Example III A mixture of l g. of Compound No. 2, 4 cc. of pyridine 1713- (2'-caproxyethylthio -3 -methoxy- A -estratriene (Cpd. No. 5) and 17,6-(2'-cyclopen-,

7 tylpropionoxyethylthio 3 methoxy-N' estratriene (Cpd. No. 6).

Example V A solution of 1 g. of Compound No. 2 in 5 cc. of pyridine was treated with 0.5 g. of tosyl chloride and kept at room temperature for 24 hours, it was then diluted with water and the precipitate separated by filtration, thus giving 175-(2-tosyloxyethylthio) 3 methoxy-A estratriene (Cpd. No. 7).

Example VI A suspension of g. of potassium fluoride in 50 cc. of dimethyl .formamide was heated to boiling and then a solution of 2 g. of Compound No. 7 in 10 cc. of dimethyl formamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The formed precipitate was filtered Off and crystallized to give 17fi-(2'- fiuoroethylthio)-3-methoxy-A -estratriene (Cpd. No. 8).

Example VII The Compound No. 7 was treated according to Example VI, except that potassium chloride was used instead of potassium fluoride, thus yielding 17/3-(2'-chloroethylthio)-3-methoxy-A -estratriene (Cpd. No. 9).

Example VIII A solution of 1 g. of Compound No. 7 in 50 cc. of dioxane was treated with a constant stream of dimethylamine during 48 hours. Thereafter, the solution was boiled under reflux for 30 minutes and poured into water,

thus affording a precipitate which was filtered oft", dried and recrystallized from methanol-benzene, thus furnishing 17,3 (2-[N,N-dimethylarnino]-ethylthio)-3-methoxy- A i -estratriene (Cpd. No. 10).

Example IX A mixture of 1 g. of Compound No. 7, 1 g. of potassium cyanide and 50 cc. of acetonitrile was kept at 100 C. for 3 hours. The mixture was then poured into water, and the formed precipitate filtered off, dried and crystallized from acetone-hexane, thus yielding 17B-(2'-cyanoethylthio)-3-methoxy-A -estratriene (Cpd. No. 11).

Example X A mixture of 1 g. of Compound No. 11, and 50 cc. of a 5% solution of sodium hydroxide in methanol, was refluxed during 4 hours, then cooled, acidified with hydrochloric acid and diluted with water. The formed precipitate was collected by filtration and recrystallized from acetone-hexane, thus yielding 17p-(2'-canboxyethylthio)- 3-methoxy-A -estratriene (Cpd. No. 12).

Example XI Example XII 1 g. of Compound No. 13 was dissolved with slow heating in 12.5 cc. of dimethyl-formamide, the mixture was cooled, 0.42 g. of mesyl chloride and 0.5 cc. of pyridine were added and the solution was kept at 80 C. for 3 hours. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 17,8-(3'-methyl but 2' enylthio) 3-methoxy A estratriene (Cpd. No. 14).

Example XIII Example XIV A cold solution of 6 g. of Compound No. 15 in 750 cc. of anhydrous ether was added to 900 cc. of liquid ammonia and then 7.8 g. of lithium wire over 10 minutes,

with constant stirring. The mixture was stirred for 20 minutes more, cc. of absolute ethanol were then cautiously added and the ammonia was allowed to evaporate. Water was added ot the residue, the ether distilled off and the resulting 17B (isoarnylthio) 3- methoxy-A -estradiene (Cpd. No. 16), collected, washed with water and dried.

A mixture containing the latter compound, 220 cc. of methanol and 132 cc. of 3 N hydrochloride acid was heated at 60 C. for 18 minutes. The solution was cooled, poured into iced water and the resulting precipitate was collected, washed with water and dried. Crystallization from acetone-hexane yielded 17(3-(isoamylthio)-A -estren-3-one (Cpd. No. 17).

Example XV The compounds Nos. 2, 3, 10 and 13, were treated according to Example XIV, thus affording respectively the following final products:

Cpd. No.:

'18. 17fl-(2'-hydroxyethylthio)-A -estren-3-one. 19. 17u- 2-hydroxyethylthio -A -estren-3-one. 20. 17B 2'- [N,N-dimethylamino -ethylthio -13 estren-3-one. 21. 17 ,8- 3 '-hydroxy-3 '-methyl-butylthio -A estren-3-one.

Example XVI The Compound No. 18 was treated successively according to Examples V and VI, thus yielding respectively: 17(3-(2-tosyloxyethylthio)-A -estren-3-one (Cpd. No. 22) and 17p-(2'-fluoroethylthio)-A -estren-3-one (Cpd. No. 23).

Example XVII The Compound No. 22 was treated according to Example VII, thus furnishing 17e-(2'-chloroethylthio)-A estren-3-one (Cpd. No. 24).

Example XVIII The Compound No. 18 was treated in accordance with Examples Nos. III and IV, thus yielding respectively: Cpd. No.:

25. 17fi-(2-acetoxyethylthio)-A -estren-3-one.

26. 176-(2'-caproxyethylthio)-A -estrene-3-one.

27. 176-(2-cyclopentylpropionoxyethylthio)-A estren-3-one.

Example XIX The Compound No. 3 was treated according to Examples III, IV and V, to produce respectively: Cpd. No.:

28. 17a- 2-acetoxyethylthio -3-methoxy-A estratriene. 29. 17oc- (2-caproxyethylthio -3-methoxy-A estratriene. 3 0. 17a-(2'-cyclopentylpropionoxyethylthio)-3- methoxy-A -estratriene.

I I Example XXVIII The Compounds Nos. 61 to 72, inclusive, were treated according to Example III, thus yielding respectively:

Upon treatment of Compounds Nos. 61 to 72, inclusive, by the procedures of Example IV, there were obtained the corresponding compounds having, respectively, caproxy groups and cyclopentylpropionoxy groups instead of acetoxy groups.

Example XXIX The Compounds Nos. 61 to 72, inclusive, were treated according to Example V, thus alfording the corresponding 17 8-(2'-tosyloxy ethylthio) derivatives, which in turn were treated in accordance with Example VI, giving respectively:

Cpd. No.:

97. 17/8-(2'fluoro ethylthio)-3-hydroxy-A estratriene,

98. 17/3-(2'-fiuoro ethylthio)-3-benzyloxy-A estratriene,

100. 17fi-(2-fluoro ethylthio)-3-n-decyloxy-A estratriene,

By treatment of the 17B-(2'-tosyloxy-ethylthio) compounds mentioned hereinbefore by the procedure of Example VII, there were produced the corresponding 17,8- (2'-chloro ethylthio) compounds.

Example XXX When treating the 17fi-(2'-tosyloxy ethylthio) compounds of Example XXIX, in accordance with Examples VIII and IX, there were produced, respectively, the cor- 12 responding 17,8-(2'-[N,N-dimethylamino] ethylthio) and 17p-(2'-cyano-ethylthio) derivatives.

The latter derivatives, in turn, were treated, successively, by the procedures described in Examples X, XI, XII, and XIII thus yielding, respectively, the corresponding 17B-(2'carboxy ethylthi0)-, l7,8-(3'-hydroxy-3'- methyl-butylthio)-, 17B-(3'-methyl-but-2'-enylthio) and 17,8-(isoamylthio)-comp0unds.

Example XXXI The reactions set forth in Examples XXVIII, XXIX and XXX for the 1 7;3-cornpounds were applied to the 17m compounds described in Example XXVII, thus yielding the corresponding 17a-isomers of the products of said examples.

Example XXXII Estrone methyl ether was treated according to Example I, except that fl-mercapto ethanol was substituted by 'y-mercapto propanol and by fi-mercapto butanol, thus yielding respectively 17-(cyclotrimethylene thiooxy)- 3-methoxy-A -estratriene (Cpd. No. 109) and 17- (cyclotetramethylene thiooxy)-3-meth0xy-A -estratriene (Cpd. No. 110). These compounds when treated by the procedure described in Example II, yielded, respectively and predominantly 17fl-(3'-hydroxy-propylthio)-3-methoxy-A -estratriene (Cpd. No. 111) and 17p (4-hydroxybutylthio)-3-methoxy A estratriene (Cpd. No. 112), and in smaller amount the corresponding Hot-isomers thereof.

Example XXXIII The starting compounds of Example XXVI were treated in accordance with Example XXXII, thus being produced the corresponding 17-(cyclotrimethylenethiooxy)- and 17-(cyclotetramethylene thiooxy) derivatives and therefrom, respectively and predominantly, the corresponding 17,8-(3-hydroxypropylthio)- and 17B-(4'-hydroxy butylthio) compounds, and in smaller amount the corresponding 17a-isomers thereof.

Example XXXIV A solution of 6 g. of Compound No. 2 in cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane afforded 17fl-(2'-oxoethylthio) 3 methoxy-M estratriene (Cpd. No. 113).

Upon treatment of the latter compound by the procedure described in Example XI, there was produced 17,6-(2'-hydroxy-propylthio) 3 methoxy-A estratriene (Cpd. No. 114). 7

Upon treatment of the latter compound by the procedure described in Example XI, there was produced 17,3-(2-hydroxy-propylthio) 3 methoxy A estratriene (Cpd. No. 114).

The Compounds Nos. 61 to 72, inclusive, were treated by the same procedures, thus yielding firstly the corresponding 17(3-(2f-oxoethylthio) derivatives and secondly, the following respective compounds.

Cpd. No.:

1 15. 17 ,8- 2-hydroxy-propylthio -3-hydroxy- A -estratriene,

1 16. 17,8- (2-hydroxy-propylthio) -3-benzyloxy- 1 17. (2'-hydroxy-propylthio -3-n-butoxy- A -estratriene,

1 18. 17 ,6- (2'-hydroxy-propylthio) -3-n-decy1oxy- A -estratriene,

1 19. 17,8- 2-hydroxy-propylthio) -3-cyclopentyloxy-A -estratriene,

120. 17fl- (2'-hydroxy-propylthio -3-isoamyloxy- A -estratriene,

Example XXX V The Compound No. 113 was treated according to Example XI, except that methyl magnesium bromide was substituted by vinyl magnesium bromide and by ethinyl magnesium bromide thus yielding respectively: 17/3-(2- hydroxy-but-3-enylthio) 3 methoxy A -estratriene (Cpd. No. 127) and 17B-(2'-hydroXy-but-3'-inyl thio)-3-methoxy-A -estratriene (Cpd. No. 128).

The rest of the 17fl-(2'-oxoethylthio) derivatives obtained in accordance with Example XXXIV were treated by the same procedures, thus yielding respectively the corresponding 17B-(2'-hydroxy-2'-vinyl-ethylthio) and 17B-(2'-hydroxy-2'-ethinyl-ethylthio) compounds.

Example XXXVI The Compounds Nos. 111, 112, 114, 127 and 128 were treated according to Example III, thus yielding respectively:

Cpd. No.:

' 129. 1713 (3 acetoxy propylthio) 3 methoxy- A -estratriene, 130. 17[3-(4'-acetoxy-butylthio)-3-methoxy-A estratriene, 131. 17 B (2 acetoxy propylthio) 3 methoxy- A -estratriene,

132. 175 (2'-acetoxy but-3'-enylthio)-3-methoxy- A -estratriene, 133. 17;? 2-acetoxy but 3-inylthio)-3-methoxy- A -estratriene,

Upon treatment of the above starting compounds in accordance with Example IV, there were obtained the corresponding caproxy and cyclopentlylpropionoxy derivatives.

Example XXXVII The Compounds Nos. 14, 111, 112, 114 and 127 were treated according to Example XIV, thus yielding respectively:

Cpd. No.:

134. 17/3 (3-methyl but-3'-enylthio)-A -estren-3- one,

135. 17,8-(3'-hydroxypropylthio)-A -estren-3-one,

136. 17/3-(4-hydroxybutylthio)-A -estren-3 one,

137. 17B-(2-hydroxypropylthio)-A -estren-3-one,

138. 17 ,B-( 2-hydroxy but 3enylthio)-A -estren-3- one.

Example XXX VIII Upon treatment of Compound No. 128 by the proce- 1 dure of Example XIV, there were produced 17 3-(2-hydr0Xy-but-3-enylthio)-A -estren-3-one (Cpd. No. 138) and 175 (2 hydroxy but-3' inylthio)-A -estren-3-one (Cpd.No. 139).

Example XXXIX The Compounds Nos. 134 to 139, inclusive, were treated according to Examples Nos. III and IV, thus affording the corresponding acetoxy, caproxy and cyclopentylpropionoxy derivatives.

1 4 Example XL To a solution of 5 g. of Compound No.13 in cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to efiect hydrolysis of the excess anhydride. The

benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 175-(3-acetoxy-3-methyl butylthio) 3-methoxy- A -estratriene (Cpd. No. By the same procedure, Compound No. 21 Was converted into 17 8-(3-acetoxy-3-methyl-butylthio) -A -estren-3-one (Cpd. No. 141

Example XLI The Compounds Nos. 114 to 128, inclusive, were treated according to Example V, thus yielding the corresponding tosyloxy derivatives, which upon treatment in accordance with Examples VI, VII, VIII, and IX atforded, respectively, the corresponding (fiuoro, chloro, N,N-dimethylamino, and cyano) 17-substituted side chain derivatives. The latter cyano compounds upon successive treatment in accordance with Examples X, XI, XII and XIII, yielded respectively the corresponding (carboxy 2-hydroxy isopropyl, isopropylidene and isopropyl) 17 substituted side chain derivatives.

I claim:

1. A compound represented by the formula:

s-R-0 R3 E 'wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms, and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms, and Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7- position.

2. A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive, and R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms.

3. 17-(2'-hydroxyethylthio)-3-methoxy-A -estratricne.

4. 17 6-(2'-hydroxyethylthio)-3-methoxy-A -estratriene.

5. 17- (2-hydroxyethylthio) -3-hydroxy-A -estrat'riene.

6. 17-(2-hydroxyethylthio)-3-benzyloxy-A -estratriene.

7. 17-(2-hydroxyethylthio)-3-n-butoxy-A -estratriene.

8. 17- 2-hydroxyethylthio -3-n-decyloXy-A estrat'riene. 9. 17-(2'-hydroxyethylthio)-3-cyclopentyloXy-A estratriene. 10. l7-(2-hydroxyethylthio)-3-isoamyloxy-A estratriene.

11. 17-(2-hydroxyethylthio)-A -estren-3-one.

12. 17- (2'-fiuoroethylthio 3-methoXy-A -estratriene.

13. 17-(2-chloroethylthio)-3-methoxy-A -estratriene.

14. 17-[2- (N,N-dimethylaniino -ethylthio]-3-methoxy- A -estratriene.

15. 17-(2-cyanoethylthio)-3-meth0xy-A -estratriene.

16. 17-(2-carboxyethylthio)-3-methoxy-A -estratriene.

17. 17-(isoamylthio)-3-methoXy-A -estratriene.

18. l7-(isoamylthio)-A -estren-3-one.

19. 17-(2-fluoroethylthio)-3-hydroxy-A -estratriene.

20. 17-(2chloroethylthio)-3-hydroxy-A -estratriene.

21. A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; X represents halogen, and Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7-position.

22. A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; X represents an N,N-dialkylamino 3 9 9 and {Z is selected tmm the group consisting of a saturated linkage and a double bond at the 6,7-position.

23. 'A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; X represents a cyano group, and Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7-position.

25. A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consistingof hydroxyl, an acyloxy group containing less than 12 carbon atoms and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; X represents an aldehydic oxygen, and Z is selected from the group consisting of 'a saturated linkage and a double bond at the 6,7-position.

26. A compound represented by the formula:

wherein R represents an aliphatic hydrocarbon residue 17 18 containing from 1 to 10 carbon atoms, inclusive, and Y wherein R represents an aliphatic hydrocarbon residue represents halogen. containing from 1 to 10 carbon atoms, inclusive, and Y 27. A compound represented by the formula: represents an N,N-dialkylarnino group.

5 References Cited in the file of this patent 3 UNITED STATES PATENTS 2,763,669 Dodson et al Sept. 18, 1956 2,840,577 Dodson et a1 June 24, 1958 

16. 17-(2''-CARBOXYETHYLTHIO)-3-METHOXY-$1,3,5(10)-ESTRATRIENE.
 23. A COMPOUND REPRESENTED BY THE FORMULA: 